Solid tumors are highly heterogeneous and contain many distinct cell types including stromal cells. We hypothesize that only subsets of the tumor cells that harbor particular aberrant signaling pathways will contribute to therapeutic response or resistance. We propose using novel multiplex single cell omics to unlock the mechanisms of complete response to ADAPT therapy, an innovative combination therapy designed to target drug-resistant (or dormant) advanced colorectal cancer likely through Wnt-PI3K-CDK axis. In this proposal, we will employ comprehensive single cell genomics, transcriptomics, and proteomics to study in vitro and in vivo the dynamic transition of tumor and stromal cells populations, before and after standard 5-FU based chemotherapy versus ADAPT therapy directly in fresh colorectal cancer biopsies samples. This study will lead to greater insight into the pathways of response and resistance to ADAPT therapy and enable the development of a transformational single cell technology (SPARTA) that simultaneously measures multiple transcripts and proteins to monitor and stratify response/resistance.